1. Josh Nooner
Endocrinology
4/29/15
Pulmonary Neuroendocrine Tumors
Lung cancer is the world’s leading cause of cancerous death, is the most frequently
occurring type of cancer for both men and women, and is normally preventable with the
cessation of smoking. One of the most common types of lung cancer is the neuroendocrine tumor
(NET). The purpose for this review is to discuss the pathology of pulmonary neuroendocrine
tumors (NETs) and to identify the major risk factors that lead to development of lung neoplasms.
Additionally, this paper will discuss how pulmonary NETs are classified, diagnosed, and the
prognosis of each type of NET. NETs are responsible for a considerable portion of all lung
neoplasms, therefore understanding the pathogenesis of NETs is very important.
To conduct this literature review I used specific search criteria. I searched for the
following keywords: neuroendocrine, tumor, pulmonary, pathogenesis, pathology, lung,
neoplasm, classification, diagnosis, prognosis, enterochromaffin, and smoking. I conducted my
search on three different search engines which were Google Scholar, PubMed, and Science
Direct. Articles were excluded if they had a publication date prior to 1990.
This paper will first discuss the major causes of pulmonary tumors and later examine the
types of lung neuroendocrine tumors and their classifications. By far, the number one cause of
lung cancer is smoking cigarettes. Secondary causes of lung cancer include second hand smoke
and exposure to environmental carcinogens, most often work related. Lastly, there are some
cases of idiopathic lung cancer where the cause is unknown. Smoking is overwhelmingly
responsible for the vast majority of lung cancer cases worldwide. There is a substantial amount
of evidence showing this fact and reinforcing the importance of eliminating smoking. Lung

2. cancer will continue to remain the number one type of cancer in the United States until we see a
drop in the number of smokers.
The first study I will discuss is titled Epidemiology of Lung Cancer and was published in
the Chest Journal in 2007. The aim of this article was to summarize the state of lung cancer
worldwide. The authors reported, “A single etiologic agent (cigarette smoking) is by far the
leading cause of lung cancer, accounting for approximately 90% of lung cancer cases in the
United States… Compared with never-smokers, smokers who have smoked without quitting
successfully have an approximate 20-fold increase in lung cancer risk… The unequivocal role of
cigarette smoking in causing lung cancer is one of the most thoroughly documented causal
relationships in biomedical research.” 1 The most thoroughly researched, documented, and
proven causal relationship for a disease is cigarette smoking in relations to lung cancer. There is
a very substantial amount of evidence highlight the devastating effects of smoking on the body
and voicing against cigarette smoking. The fact that there is still a large number of smokers,
despite the enormous body of knowledge showing the negative effects of smoking, is very eye
opening and a major cause for concern. It is paramount that smoking be eliminated in order to
reduce the incidence of lung cancer.
A study published in the Journal of the National Cancer Institute provides a great
illustration of how smoking leads to the development of lung cancer. The authors explain that
there are 20 known carcinogens in cigarettes that have been shown to cause cancer in both rats
and humans. “Of these carcinogens, polycyclic aromatic hydrocarbons and the tobacco-specific
nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone are likely to play major roles.” 2
These two carcinogens in cigarettes are the major chemicals that induce oncogenesis in
pneumocytes and other studies of carcinogens in cigarette smoke show similar findings. Figure 1

3. below illustrates the step by step process of how cigarette smoking can induce cancer formation
in the lungs. The figure explains how nicotine addiction will lead to continued cigarette smoking
Figure 1- Mutations in critical genes induced by carcinogens found in cigarette smoke 2
which leads to increased exposure to carcinogens such as PAH and NNK. These chemicals will
then act upon DNA to create DNA adducts. Sometimes the body is able to remove these
chemicals from their binding sites on DNA and there will be no DNA damage. However, when
DNA adducts persist, as with continued smoking, this will lead to miscoding of the DNA and
critical oncogenes will become activated, eventually leading to lung cancer. These steps show
the basic process of how cigarette smoking can lead to the development of lung cancer and
highlight the need to eliminate smoking. Cigarette smoking is not only toxic for the person doing
the smoking, but also for everyone around them that is exposed to the cigarette smoke.
A research article published in the British Medical Journal examined the risk of lung
cancer in lifelong non-smokers exposed to environmental tobacco smoke. After reviewing 37
epidemiological studies they concluded that, “The epidemiological and biochemical evidence on
exposure to environmental tobacco smoke, with the supporting evidence of tobacco specific
carcinogens in the blood and urine of non-smokers exposed to environmental tobacco smoke,
provides compelling confirmation that breathing other people's tobacco smoke is a cause of lung
cancer.” 3 In this study, urine and blood samples were analyzed for non-smoking individuals who
were exposed to environmental smoke and the results showed carcinogens present in both the

4. urine and blood. This article shows how cigarette smoke can cause cancer even in non-smokers.
Just being exposed to secondhand smoke increases your likelihood of developing lung cancer.
Here we see another very important reason that smoking needs to be eliminated. Smokers must
be educated about the dangers of cigarettes and the toxicity that cigarettes cause to everyone
involved.
Cigarette smoking is the number one cause of most cases of lung cancer, however there
are also a number of ways that non-smokers can increase their risks for developing lung cancer.
The main etiology of lung cancer for non-smokers is exposure to environmental hazards such as
radon, asbestos, diesel exhaust, arsenic, chromium, and silica. Researchers have identified a
handful of both environmental and occupational carcinogens. A review from the Journal of
Thoracic Disease provides us with a detailed list of all known environmental carcinogens which
is found below in Figure 2. 4 As we can see in the figure below, there are a large number of
Figure 2- Environmental Carcinogenetic Agents 4

5. cancer causing agents that humans can be exposed to through various jobs such as mining or
working in factories. There is a large need for research on the above listed chemicals in order to
help protect those who are at risk for occupational carcinogen exposure. An article out of
Clinical Cancer Research reports that, “The large numbers of current and former smokers dying
of lung cancer have obscured the important problem of lung cancer in never-smokers…The
death rate due to lung cancer in never smokers over several decades has remained relatively
constant in the US, and represents a significant ongoing public health problem…Given the
significant impact of lung cancer in never smokers, focused research on genetic and
environmental factors associated with this disease, in carefully defined and extensively
characterized populations, is warranted.” 5 This study’s conclusion points out an important fact.
So much research has been done on lung cancer in smokers that studies over lung cancer in non-
smokers has been overshadowed, leading to limited knowledge in this area. Further studies must
be conducted in order to fill this gap in the literature.
Other etiologies for lung cancer in non-smokers include a poor diet, a sedentary lifestyle,
and scarring of the lung tissue from diseases such as tuberculosis. Genetics will also play a role
for many people. For example, if an individual has a family history of lung cancer, then they are
at an increased risk for developing it as well. An individual could also have a gene mutation that
predisposes them to developing lung cancer such as multiple neuroendocrine neoplasia
syndrome, which is a hereditary gene mutation that leads to the growth of tumors in many
endocrine glands of the body. The aforementioned risk factors are the most common etiologies
of cancer development in the lungs for non-smokers, responsible for 10% of all lung cancer
cases, with smoking and exposure to secondhand smoke being responsible for the other 90% of
cases.

6. Moving along, we will now discuss the definition of a neuroendocrine tumor, the
incidence of these tumors, and why there is a critical need for more research to be conducted on
these tumors. Cancer.net tells us, “A neuroendocrine tumor begins in the hormone-producing
cells of the body’s neuroendocrine system, which is made up of cells that are a cross between
traditional hormone-producing endocrine cells and nerve cells.” 6 The neuroendocrine cells
present in the lungs are called enterochromaffin cells, also known as Kulchitsky cells.
Enterochromaffin cells of the lung are capable of producing the hormone serotonin which is
often associated with feelings of happiness. Serotonin is a neurotransmitter that is synthesized
from the amino acid tryptophan. The roles of this hormone include regulation of mood, sleeping
patterns and the circadian rhythm, and appetite control.
Kulchitsky cells are endocrine in function, and therefore unwanted fluctuations in
hormone levels are a possible side effect when tumor growth is present. Tumors in these cells
cause serotonin to be released in excess and lead to what is known as carcinoid syndrome.
Carcinoid syndrome is a set of symptoms caused by carcinoid tumors that include diarrhea, skin
flushing, abdominal pain, skin lesions on the face, and heart problems. Carcinoid syndrome is
most often caused by gastrointestinal carcinoid tumors but can also be caused by those of the
lung. Cancer.net explains that, “Symptoms of a gastrointestinal carcinoid tumor only appear if
the tumor spreads to the liver… A carcinoid tumor in the lungs causes symptoms that result from
hormones bypassing the liver and entering the bloodstream.” 7 Carcinoid tumors arising in the
gut must metastasize to the liver in order for symptoms to arise. However, when they arise in the
lungs, they are able to directly enter the blood stream and will present with the symptoms listed
above. When carcinoid tumors of the lung are symptomatic, serotonin levels will be abnormally

7. high resulting in carcinoid syndrome. Carcinoid syndrome is a potential side effect of lung
cancer, but it is generally not present with most neuroendocrine tumors.
According to Rekhtman, “Neuroendocrine tumors represent 25% of primary lung
Neoplasms…The most common lung NET is SCLC (20%), followed by LCNEC (3%), TC (2%),
and AC (0.2%).” 8 Rekhtman explains that there are 4 major classifications of neuroendocrine
tumors in the lung. These are small cell lung cancer (SCLC), large cell neuroendocrine
carcinoma (LCNEC), typical carcinoid (TC), and atypical carcinoid (AC). “Small cell lung
cancer (SCLC) is one of the fastest growing and spreading of all cancers.” 9 This type of lung
cancer will often metastasize and be found in other areas of the body. Large cell neuroendocrine
carcinomas occur less frequently and spread slower than SCLC NETs. Lung carcinoid tumors are
even rarer and also spread more slowly than the first two types of NETs. Typical carcinoid
tumors have the slowest proliferation rate of the NETs and generally does not metastasize.
However, “Atypical carcinoid tumors have a much higher mitotic rate than typical carcinoid
tumors and therefore metastasize more frequently and have a worse prognosis.” 10 As we can see,
each of these 4 subtypes of NETs have different characteristics. Because of this, the treatment
and prognosis will vary depending on which type of NET an individual is diagnosed with.
There is an ongoing debate over which method is the best to use to classify NETs.
Currently there are a number of different systems used to classify these tumors. A large amount
of variation between the systems exists which often creates confusion about how to classify these
tumors. Classification will vary greatly depending on the anatomical site that a NET arises in the
body. Dr. Klimstra explains that, “The differences in criteria have resulted in much confusion,
especially because morphologically similar tumors may be designated differently depending on
the site of origin, and some of the terminology used in one system suggests markedly different

8. tumor biology based on another system.” 11 This is an area that would benefit from additional
research over which classification system produces the most accurate diagnosis. Clarification in
the classification process will result in better diagnoses and improved prognosis for the patient.
Creating a standardized classification process will also minimize confusion amongst physicians
who use different systems and is an area that will require future studies.
One example of a classification system that has proven to be successful is described by
Dr. Huang in his original article Pulmonary Neuroendocrine Carcinomas. The purpose of his
study was to provide evidence to streamline and clarify the criteria for classifying NETs. His
team reviewed and analyzed 234 cases of primary pulmonary neuroendocrine tumors. His
conclusion was that, “Classification of pulmonary neuroendocrine carcinomas as well,
moderately, poorly differentiated, or undifferentiated provides prognostic information and avoids
misleading terms and concepts. This facilitates communication between pathologists and
clinicians and thereby improves diagnosis and management of the patient.” 12 This study suggests
that using the characteristic of differentiation as the main way to classify neuroendocrine tumors
is proving to be a promising method.
There are many ways to classify neuroendocrine tumors based on their differentiation.
According to the article Neuroendocrine Carcinomas of the Lung by Moran et al, “Tumors can
be described as histogenesis, differentiation, multidirectional differentiation, and divergent
Differentiation.” 13 While these are similar, the terms have different meanings and often get
misused. Moran continues in his article to tell us the different classification systems that have
been used to classify NETs. The first system is known as the Gould classification which is used
to define the term carcinoid. This system classified tumors as bronchopulmonary carcinoid, well-
differentiated neuroendocrine carcinoma, neuroendocrine carcinoma of intermediate-sized cells,

9. or neuroendocrine carcinoma of small cell type. The second system that has been used to classify
NETs is called the, “Bronchopulmonary Kulchitsky Cell Carcinomas (KCCs), and reverted to the
3-way classification of neuroendocrine neoplasms. This system used the designations KCC-I,
KCC-II, and KCC-III for typical carcinoid, atypical carcinoid, and small cell carcinoma,
respectively.” 13 These are just a few of the classification systems that have been used to describe
NETs.
Problems in the classification system arise from three main areas which are
nomenclature, grading, and staging. 11 Dr. Klimstra elaborates on this subject, explaining that
there are arguments over whether to use the word endocrine or neuroendocrine to describe the
origin of these tumors and whether to use the word carcinoma or tumor. Figure 3 below
highlights how these tumors are classified differently depending on the classifying
organization.11 The name given to each NET will depend on the location of the NET, the stage of
growth the tumor is in, and the grade or rate of division of the tumor.
The lung neoplasm will be identified and classified by a skilled pathologist. The
pathologist will examine the cells under a microscope and run tests on them to determine the
type, grade, and stage of the tumor. Dr. Travis, a pathologist from New York, tells us that, “The
Figure 3- Classifications of NETs by health organization 11

10. diagnosis of SCLC, TC, and AC can be made by light microscopy without the need for special
tests in most cases, but for LCNEC it is required to demonstrate NET differentiation by
immunohistochemistry or electron microscopy.” 14 Dr. Travis explains how some neoplasms
require specific tests in order to identify their type. From the work of Dr. Travis, we can see how
each type of lung NET will look under magnification. The following images are for TC, AC,
LCNEC, and SCLC NETs respectively. The images display the slight differences between the
Image 1- Typical Carcinoid NET 14 Image 2- Atypical Carcinoid NET 14
Image 3- Large Cell Neuroendocrine Carcinoma NET 14 Image 4- Small Cell Lung Cancer NET 14
four types of NETs that can be seen when viewed under a microscope. These differences allow
the pathologist to make a decision about how each NET should be classified. The classification is
very important because it will determine the subsequent diagnosis and prognosis for the patient.

11. The diagnosis for a patient is predominately dependent upon how their specific lung
neoplasm is classified. There will be a different diagnosis and treatment plan for an individual
depending on if they have a TC, AC, LCNEC, or a SCLC NET. The classification will also
determine their prognosis since there is a varying life expectancy depending on what type of
NET an individual has. For example, because SCLC tumors have a higher mitotic rate and
spread faster than the other types of tumors, this type of cancer will have the worst prognosis and
the shortest life expectancy. On the other hand, TC tumors have the slowest mitotic rate and
rarely metastasize, therefore this type of cancer will have the best prognosis and the longest life
expectance. However, there are many other factors that must be taken into consideration when
determining life expectancy such as nutritional value of the diet, smoking and drinking habits,
and any comorbidity that may exist.
Prognosis of an individual with a pulmonary neuroendocrine tumor will depend on the
type of NET present. A study out of Denmark examined the prognosis of the four subtypes of
NETs and provided us with the two year and five year prognosis for each. Skuladottir explains,
“The prognosis of patients with bronchial neuroendocrine tumors varied with the degree of
malignancy; the 5-year survival rate ranged from 87% for patients with typical carcinoids, to 44,
15 and 2% for patients with atypical carcinoids, large-cell neuroendocrine carcinoma and small-
cell carcinoma, respectively.” 15 This study further highlights the importance of identifying the
correct type of NET in order to determine the prognosis for the patient. The survival rate will
vary drastically depending on the level of malignancy. As previously discussed, the subtypes of
NETs differ in their rate of proliferation and metastasis. Listed in order from the least
proliferative to the most proliferative are TC, AT, LCNEC, and SCLC. The rate of proliferation

12. is inversely proportional to the survival rate meaning the faster the cells grow and migrate the
lower the survival rate will be. This concept is illustrated well in Table 1 below.
The outlook for a patient is directly dependent on how fast the lung neoplasm is growing
and spreading to other areas of the body. While the prognosis for TC and AC subtypes is much
greater than that of the LCNEC and SCLC subtypes, the outlook for all lung cancers is not
Type of Pulmonary Neuroendocrine Tumor TC AC LCNEC SCLC
Age at diagnosis (years) 60 64 64 66
Sex
Male (%) 49 51 58 66
Female (%) 51 49 42 34
Diagnosis; incidental finding at autopsy (%) 24 7 0 5
Extent of disease (%)
Localized 80 41 20 14
Regional 0 20 26 25
Distant 1 30 40 50
Not reported 19 9 14 11
Treated by radical resection (%) 41 36 16 1
Survival (%)
2-year 89 52 22 7
5-year 87 44 15 2
Table 1- Survival Rate for four subtypes of pulmonary neuroendocrine tumors from a Denmark study 15

13. promising. Survival rates are low for all types of lung cancer but can be increased depending
upon the stage of the cancer upon diagnosis. The American Lung Association tells us, “The five
year survival rate for lung cancer is 54.0 percent for cases detected when the disease is still
localized (within the lungs). However, only 15 percent of lung cancer cases are diagnosed at an
early stage. For distant tumors (spread to other organs) the five-year survival rate is only 4.0
percent.” 16 The reality is that lung cancer is almost always a fatal diagnosis. Currently, the
diagnosis of lung cancer mostly occurs once the cancer is in a late stage of growth. Because of
this, there are only a small majority that live for long after diagnosis. This fact is illustrated
beautifully in Figure 4. Major improvements in the medical field must be made in order to
begin to diagnose lung cancer at an earlier stage. This is one area of the literature that
consistently shows a need for further studies. If lung cancers can be detected at an earlier stage
when they are still confined to their primary sites then the survival rates of patients will increase
significantly.
There are many methods that physicians use to detect and diagnose NETs. As previously
discussed, early detection of lung cancer is critical to improving five year survival rates. One
method that has proven useful for early detection of lung cancer is discussed in an article
published in The Lancet in 2003. “This article investigated the efficacy of repeated yearly spiral
Figure 4- Lung Cancer Diagnosis and Survival by Stage 16

14. CT and selective use of positron emission tomography (PET) in a large cohort of high-risk
volunteers.” 17 The authors studied 1035 individuals who had smoked for 20 years or more. All
subjects underwent annual screening for 5 years in order to detect early cancerous growth. The
authors concluded, “We have shown that low-dose spiral CT combined with selective use of PET
can effectively detect early lung cancer.” 17 In this study, spiral computed tomography and
positron emission tomography have shown to be effective for detecting cancerous growths in the
lungs at an early stage.
A second method for diagnosing NETs at an early stage in development is examination of
sputum cytology. This method has been extensively studied for its usefulness of detecting early
development of lung cancer. According to the Mayo Clinic, “If you have a cough and are
producing sputum, looking at the sputum under the microscope can sometimes reveal the
presence of lung cancer cells.” 18 To use this method of diagnosis, doctors will take a sample of
sputum which is mucus found in the airways. The patient will undergo a bronchoscopy in order
to obtain the sputum sample. After collecting the sample, the sputum will be examined under
magnification and analyzed for the presence of cancerous cells. This is one of the most common
methods doctors use to identify the presence of lung cancer.
Another common method for diagnosis of NETs and other types of lung cancers is the
chest x-ray. This is a very common test used to examine the lungs. Strauss et al reported, “We
believe, based on the analysis presented herein, that existing data from randomized trials are
most consistent with the conclusion that periodic chest x-ray screening is beneficial, as reflected
by improvements in stage distribution, resectability, and survival.” 19 This study by the Cancer
Institute shows that x-ray increases the survival rates in patients and should be used as a standard
method for early detection of lung cancer. There are many other tests and screens that physicians

15. will utilize for early diagnosis of lung cancer including lung biopsy, thoracentesis, bone marrow
aspiration, bone scans, MRI’s, imaging tests, and molecular tests. There are a number of possible
methods that can be employed to make a diagnosis, but often times some of these methods are
controversial and not adequately supported by research.
One method believed useful for detecting lung cancer at an early stages is to measure
levels of thyroid transcription factor-1 (TTF-1). This is a great method of detection for lung
neuroendocrine tumors because it has been shown to be specific for this type of cancer. Research
has shown that this transcription factor is highly expressed in pulmonary cancer cells but not in
other anatomical sites outside of the lungs. However, counter to what was previously believed,
Agoff et al reported that, “The results of this study demonstrate that TTF-1 expression is not
limited to small cell carcinomas of the lung but may be present in small cell carcinomas of
various primary sites…The high frequency of expression of TTF-1 in extrapulmonary small cell
carcinomas strongly disputes the use of this marker to distinguish primary from metastatic small
cell carcinomas.” 20 Here we can see that there is a controversy in whether or not to use the TTF-
1 biomarker for diagnosing NETs. This study demonstrates that there is still much research
needed in this area in order to clear up confusion and to provide the necessary information
needed for practitioners to make a correct diagnosis.
In conclusion, this review has covered many topics related to pulmonary neuroendocrine
tumors focusing specifically on their etiology, how they are diagnosed and classified, and many
areas that require further research. The greatest single causes of pulmonary neoplasms is
cigarette smoking and exposure to secondhand smoke. The major causes amongst non-smokers
include environmental and occupational carcinogen exposure, genetics, diet, and a sedentary
lifestyle. There are four types of neuroendocrine tumors that vary in their rate of proliferation

16. and migration. These tumors can be classified as either typical carcinoid, atypical carcinoid,
large cell neuroendocrine carcinoma, or small cell lung carcinoma.
Lung cancer is the most frequently occurring type of cancer in the United States and is
one of the most easily preventable diseases. Smoking cessation is paramount and necessary to
reduce lung cancer incidence nationwide. Neuroendocrine tumors make up a large portion of all
cases of lung cancer and are an important area of research. There is a necessity for oncologists to
understand how to detect, classify, and diagnose this type of lung cancer. Early detection is
critical for extending the survival rate of patients diagnosed with NETs. Researchers are making
improvements in this field but there are still a number of areas that require further studies in
order to fill gaps in our knowledge base. Information over lung cancer in smokers is a field of
study that has been exhausted, but there is a need for additional research over the etiology of
lung cancer in non-smokers. Further research is also required to determine better testing
procedures that will detect cancerous growths in the lung at an early stage of growth. Lastly,
there is still a need for research over the most optimal way to classify and diagnose NETs in
order to create a single, standard protocol worldwide that will eliminate confusion between
physicians.
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